Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.

• Project/Area Number: 16K09362
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagasaki University
• Principal Investigator: AKAZAWA Yuko 長崎大学, 原爆後障害医療研究所, 准教授 (80582113)
• Co-Investigator(Kenkyū-buntansha): 中尾 一彦 長崎大学, 医歯薬学総合研究科(医学系), 教授 (00264218) ; 中島 正洋 長崎大学, 原爆後障害医療研究所, 教授 (50284683)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 非アルコール性脂肪肝炎 / NAFLD / DNA損傷応答 / 53BP1 / 発癌 / 遺伝子損傷応答 / NASH / 脂肪肝 / 線維化 / 脂肪酸 / 遺伝子不安定性 / 53Bp1 / genomic instability / carcinogenesis / 53BP-1

Outline of Final Research Achievements

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. However, the pathogenesis of hepatocellular carcinoma in NAFLD is largely unexplored. p53-binding protein 1 (53BP1), a DNA damage response molecule, accumulates at DNA double-strand break regions, forms a nuclear focus, and serves as a molecular marker of genomic instability during carcinogenesis in various malignancies. Therefore, the aim of this study was to evaluate the significance of 53BP1 expression in hepatocytes of human NAFLD. In the human liver biopsy tissues, abnormal 53-BP1 nuclear foci in hepatocytes were significantly elevated NAFLD livers, compared to normal controls (p < 0.01). Large 53BP1 foci were positively associated with pathological fibrotic score and age of patients, and negatively associated with platelet counts. These results suggest that DNA damage in hepatocytes form large 53BP1 foci in patients with NAFLD, potentially contributing to carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

NAFLDにおける肝細胞における53BP1核内フォーカス発現解析は、独特の“ゲノム不安定性”病態マーカーとして確立できる可能性がある。ヒトNAFLD肝における53BP1発現と発癌のリスクの関係が評価できれば、当手法は安価で簡便であるためNASHにおける発癌予測の指標となり、臨床診断学への応用が期待できる。

Research Products

• [Journal Article] Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. (2019)
  • Author(s): Akazawa Y, Nakashima R, Matsuda K, Okamaoto K, Hirano R, Kawasaki H, Miuma S, Miyaaki H, Malhi H, Abiru S, Itoh M, Kondo H, Fukuoka J, Nakao K, Nakashima M.
  • Journal Title: Modern pathology Volume: 印刷中 Issue: 7 Pages: 997-1007
  • DOI: 10.1038/s41379-019-0218-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression pattern of p53-binding protein 1 as a new molecular indicator of genomic instability in bladder urothelial carcinoma. (2018)
  • Author(s): Matsuda K, Kawasaki T, Akazawa Y, Hasegawa Y, Kondo H, Suzuki K, Iseki M, Nakashima M.
  • Journal Title: Scientific report Volume: 印刷中 Issue: 1 Pages: 15477-15477
  • DOI: 10.1038/s41598-018-33761-9
  • NAID: 120006987920
  • Peer Reviewed / Open Access
• [Journal Article] To die or not to die: death signaling in nonalcoholic fatty liver disease (2018)
  • Author(s): Akazawa Yuko、Nakao Kazuhiko
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 8 Pages: 893-906
  • DOI: 10.1007/s00535-018-1451-5
  • Peer Reviewed / Open Access
• [Journal Article] Ketone bodies as a predictor of prognosis of hepatocellular carcinoma after transcatheter arterial chemoembolization. (2018)
  • Author(s): Sasaki R, Taura N, Miyazoe Y, Yamamichi S, Nakashiki S, Yamashima M, Suehiro T, Honda T, Shibata H, Ozawa E, Miuma S, Akazawa Y, Miyaaki H, Matsumoto T, Nakao K, Ashizawa K.
  • Journal Title: Nutrition Volume: 57 Pages: 97-103
  • NAID: 120006988032
  • Peer Reviewed
• [Journal Article] Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice (2018)
  • Author(s): Senoo Takemasa、Sasaki Ryu、Akazawa Yuko、Ichikawa Tatsuki、Miuma Satoshi、Miyaaki Hisamitsu、Taura Naota、Nakao Kazuhiko
  • Journal Title: BMC Gastroenterology Volume: 18 Issue: 1
  • DOI: 10.1186/s12876-018-0761-7
  • NAID: 120006987314
  • Peer Reviewed
• [Journal Article] Sporadic pediatric papillary thyroid carcinoma harboring the ETV6/NTRK3 fusion oncogene in a 7-year-old Japanese girl: a case report and review of literature. (2018)
  • Author(s): Otsubo R, Mussazhanova Z, Akazawa Y, Sato A, Matsuda K, Matsumoto M, Yano H, Matsuse M, Mitsutake N, Ando T, Niino D, Nagayasu T, Nakashima M.
  • Journal Title: Endocrinol Metab Volume: 31 Issue: 4 Pages: 461-467
  • DOI: 10.1515/jpem-2017-0292
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis (2017)
  • Author(s): Takaki Hiroko、Akazawa Yuko、Kido Youko、Morishita Mami、Honda Takuya、Shibata Hidetaka、Miuma Satoshi、Miyaaki Hisamitsu、Taura Naota、Kondo Hisayoshi、Nakao Kazuhiko
  • Journal Title: Medical Science Monitor Volume: 23 Pages: 4526-4532
  • DOI: 10.12659/msm.903210
  • NAID: 120006987388
  • Peer Reviewed
• [Journal Article] Hepatitis C virus infection increases JNK phosphorylation and accentuates hepatocyte lipoapoptosis (2017)
  • Author(s): Tahaki H, Akazwa Y, et al
  • Journal Title: Med sci monnit Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice (2017)
  • Author(s): Ikuko Takahara, Yuko Akazawa, Maiko Tabuchi, Katsuya Matsuda, Hisamitsu Miyaaki, Youko Kido, Yasuko Kanda, Naota Taura, Ken Ohnita, Fuminao Takeshima, Yusuke Sakai, Susumu Egushi, Masahiro Nakashima, Kazuhiko Nakao
  • Journal Title: PLoS One Volume: 12 Issue: 3 Pages: e0170591-e0170591
  • DOI: 10.1371/journal.pone.0170591
  • NAID: 120006987538
  • Peer Reviewed / Open Access
• [Journal Article] Vonoprazan-based therapy for Helicobacter pylori eradication: experience and clinical evidence. (2016)
  • Author(s): Akazawa Y, Fukuda D, Fukuda Y.
  • Journal Title: Therap Adv Gastroenterol. Volume: 9 Pages: 845-852
  • Peer Reviewed
• [Journal Article] Expression of Somatostatin Receptor Type 2A and PTEN in Neuroendocrine Neoplasms Is Associated with Tumor Grade but Not with Site of Origin. (2016)
  • Author(s): Wada H, Matsuda K, Akazawa Y, Yamaguchi Y, Miura S, Ueki N, Kinoshita A, Yoshiura K, Kondo H, Ito M, Nagayasu T, Nakashima M.
  • Journal Title: Endocr Pathol Volume: 27 Pages: 179-87
  • Peer Reviewed
• [Presentation] Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. 53BP-1によるNAFLD肝細胞DNA損傷応答の可視性． (2019)
  • Author(s): Yuko Akazawa
  • Organizer: RONALD G. THURMAN Memorial Symposium (アルコール医学生物学研究会学術集会)
  • Int'l Joint Research / Invited
• [Presentation] 53BP1 蛍光免疫染色によるNAFLD 肝細胞遺伝子損傷応答の可視化． (2019)
  • Author(s): 赤澤祐子、宮明寿光、中尾一彦
  • Organizer: 日本肝臓学会総会
• [Presentation] H. pylori 胃炎におけるBH3-only 蛋白Bim の役割． (2019)
  • Author(s): 赤澤祐子、松田勝也、中尾一彦、中島正洋
  • Organizer: 日本病理学会総会
• [Presentation] ROLE OF p53-BINDING PROTEIN 1 IN NON-ALCOHOLIC FATTY LIVER DISEASE (2019)
  • Author(s): Hiroko Kasawaki, Yuko Akazawa, Kazuhiko Nakao
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Palmitate Induces DNA Damage Response Dependent on Oxidative Stress and Caspases in Hepatocytes. (2018)
  • Author(s): Hirano R, Akazawa Y, Matsuda K, Miyaaki H, Fukuoka J, Nakashima M, Nakao K
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Mediators of lipid metabolism and hepatocyte apoptosis in NASH: How they execute and communicate (2017)
  • Author(s): Yuko Akazawa
  • Organizer: APASL single topic
  • Place of Presentation: ハウステンボス（長崎県佐世保市）
  • Year and Date: 2017-04-11
  • Int'l Joint Research / Invited
• [Presentation] Nuclear expression of p53-binding protein 1, a DNA damage response molecule, is increased in NAFLD liver (2017)
  • Author(s): Ryoma Nakashima, Yuko Akazawa, Katsuya Matsuda, Kazuhiko Nakao, Masahiro Nakashima
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Significance of Hepatocyte Lipotoxicity in NAFLD/NASH：How the free fatty acid-mediated Signals Kill and tell (2017)
  • Author(s): Yuko Akazawa
  • Organizer: The 103rd General Meeting of the Japanese Society of Gastroenterology
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Int'l Joint Research / Invited
• [Presentation] Toyocamycin, an inhibitor of IRE1α-XBP1activation, attenuates steatosis and liver injury in high fat high carbohydrate diet-induced steatohepatitis. (2016)
  • Author(s): Tabuchi Maiko, Akazawa Yuko et al.
  • Organizer: DDW
  • Place of Presentation: サンディエゴ（アメリカ合衆国）
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] ＮASHは肝細胞核内におけるp53 binding protein-1フォーカス集積を増加させる (2016)
  • Author(s): 赤澤祐子、宮明寿光、中尾一彦
  • Organizer: 日本肝臓病学会
  • Place of Presentation: 東京ベイ幕張ホール （千葉県千葉市）